The metabolism of breast cancer metastasis to the lung: Key pathways and their implications in the metastatic microenvironment.

乳腺癌肺转移的代谢：关键途径及其在转移微环境中的影响。

• 批准号: EP/Y029232/1
• 负责人: Mariia Yuneva
• 金额: $ 25.55万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY029232%2F1
• 关键词: metabolism; breast; cancer; metastasis; lung

Metastasis is still responsible for the majority cancer-related deaths. Consequently, there is an urgent need to improve the treatment for the most aggressive cancer types, such as triple negative breast cancer. Metabolic adaptation is emerging as a hallmark to specifically target the metastatic process. According to our preliminary data, the metabolic features of breast cancer metastasis to the lungs include the upregulation of the methionine cycle, glutathione biosynthesis and a dependence on extracellular cystine. However, the interconnections between these pathways and the role they play in the lung colonisation process remain unclear. Also, the metabolic crosstalk between tumour cells and neighbouring cells in the lung microenvironment is poorly defined. Therefore, the first objective of this project is to explore the functional role of methionine and cysteine pathways in the breast metastatic cells and identify possible metabolic targets. Secondly, I aim to study the defined adaptations in the context of the lung microenvironment. To achieve that, I will use in vivo and ex vivo Myc-induced breast cancer mouse model. The metabolic vulnerabilities of the metastatic cells will be assessed using stable isotope-resolved metabolomics, genetic engineering tools and pharmacological interventions. Then, the metabolic interactions in the lung microenvironment will be defined using a unique approach that combines novel techniques such as mass spectrometry imaging, imaging mass cytometry, and single-cell RNA sequencing. Overall, the implications of this work will be the discovery of new metabolic mechanisms of metastasis that eventually contribute to the design of more efficient therapeutic approach for breast metastatic cancer.

转移仍然是大多数癌症相关死亡的原因。因此，迫切需要改善对最具侵袭性的癌症类型的治疗，例如三阴性乳腺癌。代谢适应正在成为专门针对转移过程的标志。根据我们的初步数据，乳腺癌转移到肺部的代谢特征包括甲硫氨酸循环的上调、谷胱甘肽生物合成和对细胞外胱氨酸的依赖。然而，这些途径之间的相互联系及其在肺定植过程中的作用仍不清楚。此外，肺微环境中肿瘤细胞和相邻细胞之间的代谢串扰定义不清。因此，本项目的第一个目标是探索蛋氨酸和半胱氨酸途径在乳腺转移细胞中的功能作用，并确定可能的代谢靶点。其次，我的目标是研究定义的适应在肺微环境的背景下。为了实现这一点，我将使用体内和离体Myc诱导的乳腺癌小鼠模型。将使用稳定同位素分辨代谢组学、基因工程工具和药理学干预来评估转移细胞的代谢脆弱性。然后，肺微环境中的代谢相互作用将使用一种独特的方法来定义，该方法结合了质谱成像、成像质谱细胞术和单细胞RNA测序等新技术。总的来说，这项工作的意义将是发现新的代谢机制的转移，最终有助于设计更有效的治疗方法，乳腺转移癌。